Bicyclic β-lactams intermediates having a new amino protecting group

ABSTRACT

A method for preparing a new class of protected amino intermediates is provided which utilizes reaction of an imido protected primary amine with a secondary amine. The intermediates thus provided are suitably protected for nucleophilic functionalization on the residue of the primary amine. The desired imido protected amine thus derivatized may be regenerated using acid. Further provided are methods for resolving racemic primary amines. Also provided are β-lactam intermediates protected with the new amino protecting group which are useful in the preparation of β-lactam antibiotics.

This application is a division of application Ser. No. 08/110,619, filedAug. 23, 1993 now U.S. Pat. No. 5,391,728, which is a division ofapplication Ser. No. 08/025,301, filed Mar. 2, 1993, now U.S. Pat. No.5,283,329, which is a division of application Ser. No. 07/918,196, filedJul. 22, 1992, now U.S. Pat. No. 5,239,069, which is a division ofapplication Ser. No. 07/750,214, filed Aug. 19, 1991, now U.S. Pat. No.5,169,945, which is a continuation of application Ser. No. 07/523,455,filed May 14, 1990, now abandoned.

BACKGROUND OF THE INVENTION

The literature is replete with protecting groups suitable for blocking(i.e., protecting) an amino function. For example, see Greene,Protective Groups in Organic Synthesis, pp. 218-287, John Wiley & Sons,New York (1980). There are also many examples of protecting groupssuitable for protecting an amino function in the presence of therelatively labile β-lactam moiety. The phthalimido group is one suchamino protecting group. Kukolja et al., U.S. Pat. No. 3,905,966 teachesthe utilization and removal of a 7-phthalimido function of acephalosporin via a 7-(phthalamic acid) intermediate to provide a7-amino cephalosporin. The phthalimido group is generally stable toacidic, electrophilic, and oxidative reaction conditions.

However, the base/nucleophile sensitivity of the phthalimido group iswell known. S. Wolfe et al., Canadian J. Chem., 1970, 48, 3572-3579report that hydrolysis of this imide proceeds at pH 7.4 to thephthalamic acid intermediate. Ganem et al., Tetrahedron Let., 1984, 25,2093-2096 and Uhle, J. Org. Chem., 1960, 26, 2998-3000 report that thephthalimido group reacts readily at ambient temperatures with sodiumborohydride. Many synthetic operations, for example, ester hydrolysis,enolate condensations, and alcoholysis reactions are not compatible withthe phthalimido group, because such reaction conditions would lead toundesired side-reaction with the phthalimido group. In fact, onepreferred method for the removal of a phthalimido group to provide afree primary amine consists of nucleophilic displacement with methylhydrazine.

In summary, an imido protecting group such as the phthalimido group maybe highly desirable in certain circumstances, because the primary aminewhich it protects is doubly-bonded, thus rendering it stable to avariety of reaction conditions--especially electrophilic or oxidativeconditions. However, its instability in the presence of nucleophilesseverely circumscribes its utility in synthetic organic chemistry. Thus,the present invention as discussed below provides a solution to thislong-standing problem and provides methodology for the synthetic organicchemist to utilize an imido protecting group such as a phthalimido groupas an amine-protecting group over a broader spectrum of reactionconditions necessarily encountered in a multistep synthesis, by reactingsaid imido group with a secondary amine. The acylamino group whichresults is stable to nucleophilic conditions. Thus, many desiredfunctional manipulations on the remainder of the molecule may be carriedout, and when all such nucleophilic reactions have been completed, theoriginal imido group can be regenerated using acid.

SUMMARY OF THE INVENTION

The present invention provides a process for converting a protectedamine of the formula ##STR1## wherein Q and Q' are individuallyhydrogen, C₁ -C₆ alkyl or when taken together form a divalent radical ofthe formula --CH═CH--CH═CH--; and R* is an organic residue; to compoundsof the formula ##STR2## wherein R and R⁰ are individually C₁ -C₆ alkylgroups or taken together with the nitrogen atom to which they are bondedform an optionally-substituted C₂ -C₇ nitrogen-containing ring, whichcomprises reacting the imido-protected amine with an amine of theformula HNRR⁰.

The compounds thus provided may be further derivatized on the R* radicalusing nucleophilic (especially hydrolytic) reaction conditions generallyinappropriate for utilization in the presence of an imido-protectedamine. The compounds provided above may then be treated with acid toregenerate the imide shown initially above.

As another aspect of this invention, when the R* residue contains atleast one asymmetric center, and thus the imide above is a mixture ofenantiomers (i.e., racemic), the present invention provides a method forpreparing a diasteromeric mixture by utilizing in the reaction describedabove, an amine of the formula HNRR⁰ which contains at least oneasymmetric center and exists in optically pure form. The diastereomersthus formed by this reaction may be separated using known methodology,example, by high performance liquid chromatography. Thus, in a broadsense, a method for "covalent resolution" of a racemic primary amine ofthe formula R*NH₂ is provided.

The mixture of diastereomers provided above may also be separated as afurther aspect of this invention by treatment with acid to provide theimide as described above, because the starting material is adiastereomeric mixture and the individual diastereomers react with acidto reform an imide at different rates; hence, one diastereomer can beconverted back to the imide in the presence of the other diastereomerwhich converts back to the imide much more slowly. In this manner a"kinetic resolution" of a mixture of diastereomeric acyl amines of theformula ##STR3## wherein the --NRR⁰ group contains at least oneasymmetric center and is optically pure and wherein the R* residuecontains at least one asymmetric center and exists as a mixture (i.e., aracemate), can be effected.

Further provided are novel β-lactam intermediates possessing the newamino protecting group as described above, which are useful in thesynthesis of β-lactam antibiotics.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process for preparing compounds ofFormula (1) ##STR4## wherein R and R⁰ are individually C₁ -C₆ alkylgroups or with the nitrogen atom to which they are bonded form a C₂ -C₇nitrogen-containing ring, said ring optionally substituted by one ormore C₁ -C₆ alkyl and/or C₁ -C₆ substituted alkyl groups;

Q and Q' are individually hydrogen, C₁ -C₆ alkyl or when taken togetherform a divalent radical of the formula --CH═CH--CH═CH--; and R* is anorganic residue;

which comprises reacting a compound of Formula (2) ##STR5## with anamine of the formula HNRR⁰ , wherein R, R⁰, Q, Q', and R* are as definedabove.

As a further aspect of this invention, there is provided the aboveprocess, further comprising the additional steps of

a) subjecting a compound of Formula (1): ##STR6## to nucleophilicreaction conditions, followed by b) treatment with acid to provide acompound of Formula (2): ##STR7##

In this aspect of the invention, it will be appreciated that the organicresidue R*, can be derivatized to a different R* radical by knownmethodology utilizing, inter alia, nucleophilic reaction conditions.Thus, when the R* radical of the compound of Formula (1) has beenderivatized to a desired end, the imide of Formula (2) may beregenerated by treatment with acid.

As a preferred embodiment of both of the above aspects of the presentinvention, R* is an organic residue of the formula ##STR8## wherein A isC₁ -C₆ alkyl, C₁ -C₆ substituted alkyl, --S--(C₁ -C₆ alkyl)CO₂ R", or

--CH₂ (C₁ -C₆ alkyl)CO₂ R", wherein R" is hydrogen or acarboxy-protecting group;

A' is hydrogen, an amide-protecting group, or a group of the formula--CH₂ CO₂ R"; or

A and A' taken together form a group of the formula ##STR9## wherein R²is hydrogen or a carboxy-protecting group; X is sulfur, --CH₂ --, oroxygen; and R¹ is hydrogen, hydroxy, halo, C₁ -C₄ alkoxy, C₁ -C₆ alkyl,C₁ -C₆ substituted alkyl, C₁ -C₆ alkylthio, C₁ -C₆ substitutedalkylthio, C₇ -C₁₂ phenylalkyl, C₇ -C₁₂ substituted phenylalkyl, phenylor substituted phenyl; a group of the formula

    --COR.sup.3

wherein

R³ is hydrogen, C₁ -C₆ alkyl, C₁ -C₆ substituted alkyl, C₇ -C₁₂phenylalkyl, C₇ -C₁₂ substituted phenylalkyl, phenyl, substitutedphenyl, amino, (monosubstituted) amino, or ( disubstituted )-amino; agroup of the formula

    --COOR.sup.4

wherein

R⁴ is hydrogen, C₁ -C₆ alkyl, C₁ -C₆ substituted alkyl, C₇ -C₁₂phenylalkyl, C₇ -C₁₂ substituted phenylalkyl, phenyl, substitutedphenyl, or a carboxy-protecting group.

As a further preferred embodiment of both of the above aspects of thepresent invention, the amine of the formula HNRR⁰ utilized abovepossesses at least one asymmetric center and exists in optically pureform, thereby providing a compound of the formula ##STR10## wherein Q,Q', and R* are as described above, and the organic residue, R*, containsat least one asymmetric center and exists as a racemic mixture. Thediastereomers provided thereby may be separated using known methodology.For example, since diastereomers, by definition differ in physicalproperties, they may be separated using any known physical separationmethod, for example liquid chromatography, preparative thin layerchromatography, or by selective crystallization of one diastereomer. Asto the use of the terms diastereomer, racemate, and enantiomer, saidterms will be used in their normal context to describe thestereochemistry of discrete compounds of formulae (1) and (2). Theseterms will also be used to address the stereochemistry of the individualgroups --NRR⁰ and --R* which comprise portions of compounds of theformulae (1) and (2). For example, when the --NRR⁰ group above isreferred to as an enantiomer, or is said to possess at least oneasymmetric center in optically pure form, the --R* group is referred toas a racemate, the discrete compound above will be referred to as adiastereomer.

As a preferred embodiment of this aspect of the invention, R* is anorganic residue of the formula ##STR11## wherein A is C₁ -C₆ alkyl, C₁-C₆ substituted alkyl, --S--(C₁ -C₆ alkyl)CO₂ R", or

--CH₂ (C₁ -C₆ alkyl)CO₂ R", wherein R" is hydrogen or acarboxy-protecting group; and

A' is hydrogen, an amide-protecting group, or a group of the formula--CH₂ CO₂ R"; or

A and A' taken together form a group of the formula ##STR12## wherein R²is hydrogen or a carboxy-protecting group; X is sulfur, --CH₂ --, oroxygen; and R¹ is hydrogen, hydroxy, halo, C₁ -C₄ alkoxy, C₁ -C₆ alkyl,C₁ -C₆ substituted alkyl, C₁ -C₆ alkylthio, C₁ -C₆ substitutedalkylthio, C₇ -C₁₂ phenyl-alkyl, C₇ -C₁₂ substituted phenylalkyl,phenyl, or substituted phenyl; a group of the formula

    --COR.sup.3

wherein

R³ is hydrogen, C₁ -C₆ alkyl, C₁ -C₆ substituted alkyl, C₇ -C₁₂phenylalkyl, C₇ -C₁₂ substituted phenylalkyl, phenyl, substitutedphenyl, amino, (monosubstituted amino, or (disubstituted)amino; a groupof the formula

    --COOR.sup.4

wherein

R.sup. 4 is hydrogen, C₁ -C₆ alkyl, C₁ -C₆ substituted alkyl, C₇ -C₁₂phenylalkyl, C₇ -C₁₂ substituted phenylalkyl, phenyl, substitutedphenyl, or a carboxy-protecting group.

In a further aspect of the present invention, there is provided aprocess for preparing compounds of the formulae ##STR13## wherein Q andQ' are individually hydrogen, C₁ -C₆ alkyl, or when taken together forma divalent radical of the formula --CH═CH--CH═CH--; R and R⁰ areindividually C₁ -C₆ alkyl groups or with the nitrogen atom to which theyare bonded form a C₂ -C₇ nitrogen containing ring, said ring optionallysubstituted by one or more C₁ -C₆ alkyl and/or C₁ -C₆ substituted alkylgroups; said R and R⁰ groups together possessing a sum of at least oneasymmetric center in optically pure form; R*^(E) is an organic residuecontaining at least one asymmetric center, said organic residue inoptically pure form; which comprises reacting a compound of the formula##STR14## with acid, wherein R and R⁰ are as defined above; and whereinR* is an organic residue R*^(E) as defined above, however in racemicform; followed by separating compound (A) from compound (B). It will beappreciated by one of ordinary skill in the art that the reactiondepicted above provides a mixture of products which is enhanced inenantiomeric purity of the starting material of one isomer and thering-closed or imido form of the corresponding opposite isomer relativeto the racemic starting material. Thus, since the diastereomers reactwith acid at different rates, (i.e., each possesses different reactionkinetics), enantiomerically enhanced solutions of one enantiomer can begenerated by monitoring the reaction mixture and isolating the desiredproduct at the appropriate point to maximize yield and optical purity.Thus, because the component diastereomers of the formula ##STR15## reactwith acid at different rates, a "kinetic resolution" of one imidodiastereomer can be effected. Since one acyl-protected diastereomerconverts back to its corresponding imido form at a faster rate, the twoproducts can be differentiated and either crystallized out of solutionselectively or separated by physical methods. While one diastereomerreacts with acid to form the imido derivative, the other diastereomeralso reacts, but at a slower rate, and if the kinetics of the reactionare monitored and isolation carried out accordingly, one can obtain animido or acyl protected compound of either formula above which isenhanced in enantiomeric or diastereomeric purity, respectively.

As a preferred embodiment of the above aspect of the present inventionR* is a racemic mixture of the formulae ##STR16## wherein A is C₁ -C₆alkyl, C₁ -C₆ substituted alkyl, --S--(C₁ -C₆ alkyl)CO₂ R", or --CH₂ (C₁-C₆ alkyl)CO₂ R", wherein R" is hydrogen or a carboxy-protecting group;A' is hydrogen, an amide-protecting group, or a group of the formula--CH₂ CO₂ R"; or A and A' taken together form a group of the formula##STR17## wherein R² is hydrogen or a carboxy-protecting group; X issulfur, --CH₂ --, or oxygen; and R¹ is hydrogen, hydroxy, halo, C₁ -C₄alkoxy, C₁ -C₆ alkyl, C₁ -C₆ substituted alkyl, C₁ -C₆ alkylthio, C₁ -C₆substituted alkylthio, C₇ -C₁₂ phenylalkyl, C₇ -C₁₂ substitutedphenylalkyl, phenyl or substituted phenyl; a group of the formula

    --COR.sup.3

wherein

R³ is hydrogen, C₁ -C₆ alkyl, C₁ -C₆ substituted alkyl, C₇ -C₁₂phenylalkyl, C₇ -C₁₂ substituted phenylalkyl, phenyl, substitutedphenyl, amino, (monosubstituted) amino, or (disubstituted)-amino; agroup of the formula

    --COOR.sup.4

wherein

R⁴ is hydrogen, C₁ -C₆ alkyl, C₁ -C₆ substituted alkyl, C₇ -C₁₂phenylalkyl, C₇ -C₁₂ substituted phenylalkyl, phenyl, substitutedphenyl, or a carboxy-protecting group.

In the above formulae, the term "organic residue" (R*) refers to anyhydrocarbyl radical optionally substituted with any variety offunctional groupings not limited to those discussed herein. In thisregard, one of ordinary skill in the art of synthetic organic chemistrywill appreciate that the invention herein expands the utility of imidoprotecting groups, preferably the phthalimido group, in conjunction withsynthetic manipulations on a substrate of the formula R*NH₂. One ofordinary skill will appreciate that the R* radical can be literally anyresidue of a primary amine R* NH₂. For example, R*NH₂ can be a 6-aminopenicillinic acid, a 7-amino-3-cephem, a 7-amino1-carba(1-dethia)cephem, a 6-amino-penam, a 3-amino monocyclic β-lactamor a 7-amino-1-oxo(1-dethia)cephem. Further, R* may be a residue of amacrolide or tetracycline antibiotic, a steroid, or a leukotriene. Thus,the identity of R* is not crucial so long as it represents an organicresidue upon which one or more synthetic manipulations, includingnucleophilic reactions may be desired.

The term "C₁ -C₆ alkyl" denotes such groups as methyl, ethyl, n-propyl,iso-propyl, n-butyl, sec-butyl, tert-butyl, amyl, tert-amyl, hexyl andthe like. The preferred "C₁ -C₆ alkyl" group is methyl.

The term "C₁ -C₆ substituted alkyl" denotes the above C₁ -C₆ alkylgroups having one or two substituents selected from halogen, hydroxy,protected hydroxy, amino, protected amino, C₁ -C₇ acyloxy, nitro,carboxy, protected carboxy, carbamoyl, carbamoyloxy, cyano,methylsulfonylamino or C₁ -C₄ alkoxy groups.

Examples of the above substituted alkyl groups are the cyanomethyl,nitromethyl, hydroxymethyl, trityloxymethyl, propionyloxymethyl,aminomethyl, carboxymethyl, allyloxycarbonylmethyl,allyloxycarbonylaminomethyl, carbamoyloxymethyl, methoxymethyl,ethoxymethyl, t-butoxymethyl, acetoxymethyl, chloromethyl, bromomethyl,iodomethyl, 6-hydroxyhexyl, 2,4-dichloro(n-butyl), 2-amino(iso-propyl),2-carbamoyloxyethyl and the like. A preferred group of examples withinthe above "C₁ -C₆ substituted alkyl" group are the substituted methylgroup, e.g., a methyl group substituted by the same substituents as the"C₁ to C₆ substituted alkyl" group. Examples of the substituted methylgroup include groups such as hydroxymethyl, protected hydroxymethyl,(e.g., tetrahydropyranyloxymethyl), acetoxymethyl, carbamoyloxymethyl,chloromethyl, bromomethyl and iodomethyl.

The term "C₁ -C₄ alkoxy" as used herein denotes groups such as methoxy,ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy and like groups. Theterm "C₁ -C₇ acyloxy" denotes herein groups such as formyloxy, acetoxy,propionyloxy, butyryloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy, andthe like. Similarly, the term "C₁ -C₇ acyl" encompasses groups such asformyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl,benzoyl and the like.

The term "substituted phenyl" specifies a phenyl group substituted withone or two moieties chosen from the group consisting of halogen,hydroxy, protected hydroxy, cyano, nitro, C₁ -C₆ alkyl, C₁ -C₄ alkoxy,carboxy, protected carboxy, carboxymethyl, protected carboxymethyl,hydroxymethyl, protected hydroxymethyl, aminomethyl, protectedaminomethyl, trifluoromethyl or N-(methylsulfonylamino).

Examples of the term "substituted phenyl" are a mono- or di(halo)phenylgroup such as 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl,3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl,3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2-fluorophenyl and the like;a mono- or di(hydroxy)phenyl group such as 4-hydroxyphenyl,3-hydroxyphenyl, 2,4-dihydroxyphenyl, the protected-hydroxy derivativesthereof and the like; a nitrophenyl group such as 3- or 4-nitrophenyl; acyanophenyl group, for example, 4-cyanophenyl; a mono- or di(lower alkyl)phenyl group such as 4-methylphenyl, 2,4-dimethylphenyl,2-methylphenyl, 4- (iso-propyl )phenyl, 4-ethylphenyl,3-(n-propyl)phenyl and the like; a mono- or di(alkoxy)phenyl group, forexample, 2,6-dimethoxyphenyl, 4-methoxyphenyl, 3-ethoxyphenyl,4-(iso-propoxy)phenyl, 4-(t-butoxy)phenyl, 3-ethoxy-4-methoxyphenyl andthe like; 3- or 4- trifluoromethylphenyl; a mono- or dicarboxyphenyl or(protected carboxy)phenyl group such as 4-carboxyphenyl or2,4-di(protected carboxy )phenyl; a mono- or di(hydroxymethyl)phenyl or(protected hydroxymethyl)phenyl such as 3-(protected hydroxymethyl)phenyl or 3,4-di(hydroxymethyl)phenyl; a mono- or di(aminomethyl)phenyl or (protected aminomethyl)phenyl such as 2-(aminomethyl)phenylor 2,4-(protected aminomethyl)phenyl; or a mono- ordi(N-(methylsulfonylamino))phenyl such as3-(N(methylsulfonylamino))phenyl. Also, the term "substituted phenyl"represents disubstituted phenyl groups wherein the substituents aredifferent, for example, 3-methyl-4-hydroxyphenyl,3-chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl,4-ethyl-2-hydroxyphenyl, 3-hydroxy-4 -nitrophenyl,2-hydroxy-4-chlorophenyl and the like. Preferred substituted phenylgroups include the 2- and 3-trifluoromethylphenyl, the 4-hydroxyphenyl,the 2-aminomethylphenyl and the 3-(N-(methylsulfonylamino))phenylgroups.

The terms "halo" and "halogen" refer to the fluoro, chloro, bromo oriodo groups. Chloro is preferred.

The terms C₁ -C₆ alkylthio and C₁ -C₆ substituted alkylthio denote C₁-C₆ alkyl and C₁ -C₆ substituted alkyl groups, respectively, attached toa sulfur which is in turn the point of attachment for the C₁ -C₆alkylthio or C₁ -C₆ substituted alkylthio group.

The term "C₇ -C₁₂ phenylalkyl" denotes a C₁ -C₆ alkyl group substitutedat any position by a phenyl ring. Examples of such a group includephenyl methyl (benzyl), 2-phenylethyl, 3-phenyl-(n-propyl ),4-phenylhexyl, 3-phenyl-(n-amyl), 3-phenyl-(sec-butyl), and the like. Apreferred group is the benzyl group.

The term "C₇ -C₁₂ substituted phenylalkyl" denotes a C₇ -C₁₂ phenylalkylgroup substituted on the C₁ -C₆ alkyl portion with one or two groupschosen from halogen, hydroxy, protected hydroxy, amino, protected amino,C₁ -C₇ acyloxy, nitro, carboxy, protected carboxy, carbamoyl,carbamoyloxy, cyano, C₁ -C₆ alkylthio, N-(methylsulfonylamino) or C₁ -C₄alkoxy; and/or the phenyl group may be substituted with 1 or 2 groupschosen from halogen, hydroxy, protected hydroxy, nitro, C₁ -C₆ alkyl, C₁-C₄ alkoxy, carboxy, protected carboxy, carboxymethyl, protectedcarboxymethyl, hydroxymethyl, protected hydroxymethyl, aminomethyl,protected aminomethyl, or an N-(methylsulfonylamino) group. As before,when either the C₁ -C₆ alkyl portion or the phenyl portion or both aredisubstituted, the substituents can be the same or different.

Examples of the term "C₇ -C₁₂ substituted phenyl alkyl" are groups suchas 2-phenyl-1-chloroethyl, 2-(4-methoxyphenyl)ethyl,2,6-dihydroxy-4-phenyl (n-hexyl), 5-cyano-3-methoxy-2-phenyl(n-pentyl),3-(2,6-dimethylphenyl)n-propyl, 4-chloro-3-aminobenzyl,6-(4-methoxyphenyl)-3-carboxy(n-hexyl),(5-(4-aminomethylphenyl)-3-(aminomethyl) (n-pentyl), and the like.

The term "(monosubstituted)amino" refers to an amino group with onesubstituent chosen from the group consisting of phenyl, substitutedphenyl, C₁ -C₆ alkyl, and C₇ -C₁₂ phenylalkyl, wherein the latter threesubstituent terms are as defined above.

The term "(disubstituted)amino" refers to amino groups with twosubstituents chosen from the group consisting of phenyl, substitutedphenyl, C₁ -C₆ alkyl, and C₇ -C₁₂ phenylalkyl wherein the latter threesubstituent terms are as described above. The two substituents can bethe same or different.

The term "carboxy-protecting group" as used herein refers to one of theester derivatives of the carboxylic acid group commonly employed toblock or protect the carboxylic acid group while reactions are carriedout on other functional groups on the compound. Examples of suchcarboxylic acid protecting groups include 4-nitrobenzyl,4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl,2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl,3,4-methylene-dioxybenzyl, benzhydryl, 4,4'-dimethoxybenzhydryl, 2,2',4,4'-tetramethoxybenzhydryl, t-butyl, t-amyl, trityl, 4-methoxytrityl,4,4'-dimethoxytrityl, 4,4',4"-trimethoxytrityl, 2-phenylprop-2-yl,trimethylsilyl, t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl,β-(trimethylsilyl)ethyl, β-(di(n-butyl)methylsilyl)ethyl,p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl,1-(trimethylsilylmethyl)prop-1-en-3-yl, and like moieties. The speciesof carboxy-protecting group employed is not critical so long as thederivatized carboxylic acid is stable to the condition of subsequentreaction(s) on other positions of the molecule and can be removed at theappropriate point without disrupting the remainder of the molecule.Preferred carboxylic acid protecting groups are the allyl andp-nitrobenzyl groups. Further examples of these groups are found in E.Haslam, "Protective Groups in Organic Chemistry", J. G. W. McOmie, Ed.,Plenum Press, New York, N.Y., 1973, Chapter 5, and T. W. Greene,"Protective Groups in Organic Synthesis", John Wiley and Sons, New York,N.Y., 1981, Chapter 5. A related term is "protected carboxy", whichrefers to a carboxy group substituted with one of the abovecarboxy-protecting groups.

As used herein, the term "amide-protecting group" refers to any grouptypically used in the β-lactam art for protecting the β-lactam ringnitrogen from undesirable side reactions. Such groups includep-methoxyphenyl, 3,4-dimethoxybenzyl, benzyl, O-nitrobenzyl,di-(p-methoxyphenyl)methyl, triphenylmethyl,(p-methoxyphenyl)diphenylmethyl, diphenyl-4-pyridylmethyl,m-2-(picolyl)-N'-oxide, 5-dibenzosuberyl, trimethylsilyl, t-butyldimethylsilyl, and the like. Further descriptions of protecting groupsdenoted by this term can be found in "Protective Groups in OrganicSynthesis", by Theodora W. Greene, 1981, John Wiley & Sons, New York.

In the amine of formula HNRR⁰ , as defined above, one of ordinary skillwill appreciate that the R and R⁰ groups should be chosen in order toprovide an amine of sufficient nucleophilic character. In other words,if R and R⁰ are relatively large or bulky groups, the amine of formulaHNRR⁰ could be significantly sterically hindered and thus nonreactivewith the carbonyl moiety of compounds of Formula (2). Examples of usefulamines of the formula HNRR⁰ are aziridine, azetidine, pyrrolidine,piperidine, dimethylamine, diethylamine, dipropylamine, dibutylamine,dipentylamine, dihexylamine, dihextylamine, methyl hextylamine, ethylhexylamine and the like. Further, one of ordinary skill will appreciatethat this amine may be used as a reagent in homogeneous form, or may becovalently immobilized on a solid support matrix using knownmethodology.

A further preferred group of amines of the formula HNRR⁰ are those whichpossess at least one asymmetric center and are in optically pure form.Accordingly, when an optically active compound of the formula HNRR⁰ isreacted with a compound of Formula (2), the resulting compound ofFormula (1) will exist as a mixture of diastereomers, which,consequently differ in physical and chemical properties. This differencein physical properties allows the component diastereomers to beseparated by known physical separation methods such as liquidchromatography, preparative thin layer chromatography, or by selectivecrystallization of one isomer away from the other. The difference inchemical properties exhibits itself in the relative reactivity that thediastereomers of Formula (1) react with acid.

As described herein, compounds of Formula (1) can be converted back to acompound of Formula (2) by treatment with acid. In this aspect of theprocess, the term "acid" refers to any strong mineral acid, for example,HCl.

A B(OH)₃ /HF mixture in tetrahydrofuran/water is preferred although itwas found that B(OH)₃ and HF individually did not effect the conversionof the acyl derivative back to the imido protected form.

Amines of the formula HNRR⁰ that possess an asymmetric center arereadily identified by one of ordinary skill in organic chemistry.Illustrative of such amines are the following: 2-chloropropylamine,2-methyl azetidine, methyl-(2-methyl)propylamine, 2-methyl pyrrolidine,3-amino-pentyne, 2-cyclopropyl ethylamine, methylbenzylamine,2-methoxymethyl pyrrolidine and 2-carboxamido-3-pyrrolidine.

In the above process suitable solvents include, in general, polar orapolar, non-protic, non-amino-reactive, non-basic, non acidic reagents,for example, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, ordimethylsulfoxide. Methanol, water, and CH₂ Cl₂ were found to beunsuitable in the above process.

The above process is ideally carried out at a temperature from about 0°C. to about 70°-80° C., depending upon the reactivity of the amine(HNRR⁰) and the particular imido substrate of Formula (2).

As an illustration of how the process of the present invention can beutilized, scheme below sets forth a sequence useful for the totalsynthesis of 1-carba(dethia)-3-cephems. Further provided below are novelintermediates utilizing the new protecting group taught herein.##STR18##

In the above scheme, the epoxy aldehyde and the t-butyl glycine (R" is acarboxy protecting group) can be condensed to form imine (A), using acommon dehydrating agent such as anhydrous MgSO₄ or molecular sieves.The resulting imine (A) can then be reacted with phthaloylglycylchloridein the presence of a base such as triethylamine. In the ensuing "2+2"(ketene+imine) cycloaddition, azetidinone (B) is provided in highenantiomeric purity. Further details of this sequence are taught byEvans et al., European Patent Application No. 89302778.9, PublicationNo. 0334593.

The azetidinone (B) can then be deoxygenated to form the olefin (C),which, in turn, may be hydrogenated to intermediate (D). Intermediate(D) can then be selectively deesterified with trifluoroacetic acid toyield intermediate (E). Intermediate (E) can then be reacted with asecondary amine of the formula HNRR⁰ in the process of the invention toprovide intermediate (F), thereby yielding an azetidinone intermediatewith a protected 3-amino function which is stable under reactionconditions normally considered inappropriate in the presence of aphthalimido group, i.e., reactions with nucleophiles, especiallyhydrolytic type reactions.

Further, intermediate (F) can be desterified to provide the diacidintermediate (G), which can, in turn be reesterified to form the phenyldiester (H). The p-nitrobenzyl ester (I) can then be provided byselective transesterification of (H) with p-nitrobenzyl alcohol and acatalytic amount of an alkoxide, such as potassium or sodium t-butoxide.

Finally, the 3-enol intermediate (J) can be generated by reactingintermediate (I) with 3 equivalents of sodium t-butoxide intetrahydrofuran. Further details of the cyclization can be found incopending U.S. Ser. No. 07/405,602, incorporated herein by reference.Cleavage of the p-nitrophenyl ester (K) into the acid (L) can beaccomplished by the well-known method hydrogenation in acetic acid andtetrahydrofuran in the presence of palladium. The 3-enol derivative (J)can then be chlorinated with triphenylphosphitedichloride/pyrimidine inmethylene chloride and ethyl acetate as taught by Bodurow et al.,Tetrahedron Let. 1989, 30, 2321; the HCl present also effects theconversion of the 7-acyl group to the 7-phthalimido group to provide(K). The p-nitrobenzyl ester (K) can be removed by utilizing Pd/Ccatalyzed hydrogenation as is well-known in the art to provide (L).Hydrazinolysis of the phthalimido intermediate (L) into (M) has beenreported by Hirata et al., Chem. Pharm. Bull. Jap. 1989, 37, 1239.

The resulting 7-β amino-1-carba(dethia)-3-chloro-3-cephem-4-carboxylicacid (M) can then be acylated with an activated form of phenylglycineusing known methodology to provide the antibiotic, loracarbef,7-β-(D-phenyl-glycylamido)-1-carba(dethia)-3-chloro-3-cephem-4carboxylicacid. Further details of these manipulations may be found in U.S. Pat.No. 4,708,956, incorporated herein by reference.

As a further aspect of the invention, there are provided compounds ofthe formula ##STR19## wherein R* is a group of the formula ##STR20##wherein R and R⁰ are individually C₁ -C₆ alkyl groups or with thenitrogen atom to which they are bonded form a C₂ -C₇ nitrogen-containingring, said ring optionally substituted by one or more C₁ -C₆ alkyland/or C₁ -C₆ substituted alkyl groups;

Q and Q' are individually hydrogen, C₁ -C₆ alkyl, or when taken togetherform a divalent radical of the formula --CH═CH--CH═CH--;

A is C₁ -C₆ alkyl, C₁ -C₆ substituted alkyl, --S--C₁ -C₆ alkyl)CO₂ R",or --CH₂ (C₁ -C₆ alkyl)CO₂ R" wherein R" is hydrogen or acarboxy-protecting group;

A' is hydrogen, an aide-protecting group, or a group of the formula--CH₂ CO₂ R"; or

A and A' taken together form a group of the formula ##STR21## wherein R²is hydrogen or a carboxy-protecting group; X is sulfur, --CH₂ --, oroxygen;

R¹ is hydrogen, hydroxy, halo, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, C₁ -C₆substituted alkyl, C₁ -C₆ alkylthio, C₁ -C₆ substituted alkylthio, C₇-C₁₂ phenylalkyl, C₇ -C₁₂ substituted phenylalkyl, phenyl or substitutedphenyl; a group of the formula

    --COR.sup.3

wherein

R³ is hydrogen, C₁ -C₆ alkyl, C₁ -C₆ substituted alkyl, C₇ -C₁₂phenylalkyl, C₇ -C₁₂ substituted phenylalkyl, phenyl, substitutedphenyl, amino, (monosubstituted)-amino, or (disubstituted)- amino; agroup of the formula

    --COOR.sup.4

wherein

R⁴ is hydrogen, C₁ -C₆ alkyl, C₁ -C₆ substituted alkyl, C₇ -C₁₂phenylalkyl, C₇ -C₁₂ substituted phenylalkyl, phenyl, substitutedphenyl, or a carboxy-protecting group.

As a further aspect of the present invention, there are provided novelcompounds F, G, H, I and J as depicted in the scheme above which utilizethe new protecting group taught herein and are useful in preparing theβ-lactam antibiotic, loracarbef. A preferred aspect of this aspect ofthe invention is the above group of compounds in which R and R⁰ aretaken together and, along with the nitrogen atom to which they areattached form a pyrrolidino ring. Phthalimido-protected intermediates C,D, and E, above, are also provided as a further aspect of the inventionand are useful in preparing intermediate F as well as expanding theutility of the Evans chiral epoxide methodology referred to in step 1 ofthe above scheme, since by virtue of the discovery of the presentinvention, a phthalimido group may be used in the beginning stages ofthe above scheme, then converted to the new acyl protecting group beforethe nucleophilic cyclization to (J), and then converted back to aphthalimido-protected intermediate (K). Thus, the present inventionallows one to use the highly desirable phthalimido group in thecycloaddition, and avoid complete removal of the phthalimido group,followed by reprotection with a different protecting group that would bestable under the conditions providing intermediate (J).

EXPERIMENTAL SECTION Preparation 1

(2-ethoxycarbonyl)-(1-formyl)ethylene oxide

The procedure described by Evans and Williams European PatentApplication No. 89302778.9, Publication No. 0334593 was employed for theSwern oxidation of (2-ethoxycarbonyl)-(1-hydroxymethyl) ethylene oxide(5.00 g) in methylene chloride (total 170 ml) with dimethylsulfoxide(7.3 mL), oxalyl chloride (4.2 mL) and triethylamine. Extractive work-upinvolving brine (150 mL), followed by trituration of impurities withpentane-ethyl acetate (2: 1, 450 mL ) afforded the title aldehyde (4.0g, 80%). This material is used immediately and/or stored in drymethylene chloride at -25° C. under nitrogen.

TLC: Rf, 0.49 (ethyl acetate-petroleum ether, 1:1). ¹ H NMR (CDCl₃): δ1.30 (t,J=7.2, 3H), 3.59 (dxd, J=1.5 and 6.4, 1H), 3.73 (d, J=1.5, 1H),4.26 (m, 2H), 9.03 (d, J=6.4, 1H).

Reaction with 2,4-dinitrophenylhydrazone produced a compound with MS(FD) m/z=324.

EXAMPLE 1

1-t-butoxycarbonyl-3-β-phthaloylamino-4β-(2-ethoxycarbonyl) ethyleneoxide-1-yl-azetidin-2-one

The process described by Evans, European Patent Application No.89302778.9 was employed to convert the unstable epoxide from Preparation1 (4.5 g in 167 mL of methylene chloride) into the intermediate iminewith t-butylglycinate (45 mL of a 0.684M solution in methylene chloride)using 4Å molecular sieves (25 g, 0 ° , 1 h). Immediate reaction of thisimine solution with phthalimidoacetylchloride (6.97 g in 100 mL ofmethylene chloride) and triethylamine (4.74 g; -78° C. for 15 minutesthen -20° C. for 18 hr) followed by extractive work-up (water and sodiumbicarbonate) and recrystallization from ethyl acetate-hexane affordedthe title compound (6.50 g) as colorless needles.

IR (CHCl₃): 1782.7, 1775, 1726.9 cm⁻¹. mp. 187.5-189° C. TLC: Rf, 0.45(diethylether ). Elem. Analysis Calculated for C₂₂ H₂₄ N₂ O₈ C, 59.46;H, 5.44; N 6.30. Found: C, 59.62; H, 5.44; N, 6.25 ¹ H NMR (CDCl₃):δ7.87 (m, 2H), 7.78 (m 2H), 5.63 (d, 1H), 4.13 (dxd, 2H), 3.90 (m, 2H),3.63 (m, 1H) 3.51 (dxd, 1H), 3.16 (d, 1H), 151 (s, 9H), 0.83 (t, 3H)

Diastereomeric purity was established by examination of the ¹ H NMR (500MHz) in CDCl₃ and DMSO-d₆ in the presence of europium Opti-shift®,2,2,2-trifluoroanthrylethanol, and mandelic acid. No peak doubling wasseen in any other of the above experiments.

¹³ C NMR(CDCl₃): δ 14.59, 29.05, 44.56, 56.18, 57.43, 61.94, 62.57,84.19, 124.85, 132.51, 135.72, 164.77, 167.46, 167.95, 168.08.

EXAMPLE 2

1-t-Butoxycarbonylmethyl-3-β-phthaloylamino-4β-(2ethoxycarbonyl)ethane-1-yl-azetidin-2-one

The epoxide from Example 1 (7.25 g) in acetonitrile (100 mL) was treatedwith sodium iodide (4.9 equiv.) and then p-toluenesulfic acid (12.5 g inacetonitrile added at 3° C. over 2 h). Extractive work-up involvingethyl acetate (800 mL), saturated aqueous sodium bicarbonate (100 mL),aqueous sodium thiosulfate (10%, 4×100 mL), brine (100 mL ), and sodiumsulfate (as a drying agent ) provided the unsaturated ester (white foam,6.55 g, 94%) after evaporation of the dried extracts.

TLC: Rf, 0.5 (one spot, ethyl acetate-hexane, 1:1) [α]₅₈₉ =+34.17° (c=1,MeOH) [α]₃₆₅ =+85.32° (C=1, MeOH) Analysis: Calculated for C₂₂ H₂₄ N₂ O₇Calc.: C, 61.68; H, 5.65; N, 6.54; Found: C, 60.70; H, 5.20; N, 6.28. ¹³C NMR (CDCl₃): δ 14.06, 28.08, 43.00, 58.75, 59.70, 60.72, 83.09,123.88, 128.08, 131.54, 134.59, 134.66, 139.88, 163.83, 164.79, 166.66,166.93. ¹ H NMR (CDCl₃): δ 7.87 (m, 2H), 7.83 (m, 2H), 6.87 (dxd, 1H),6.10 (dxd, 1H), 5.67 (d, 1H), 4.84 (dxd, 1H), 4.38 (d, 1H), 4.10 (q,2H), 3.69 (d, 1H), 1.47 (s, 9H), 1.18 (t, 3H).

EXAMPLE 3

1-t-Butoxycarbonylmethyl-3β-phthaloylamino-4β-(2-ethoxycarbonyl)ethan-1-yl

The unsaturated ester from Example 2 (0.5 g) was hydrogenated, (1 atm.hydrogen, 25° C., 2.5 h) with palladium on carbon (5% w/w, 0.5 g) inethanol after which the solution was filtered and evaporated to providethe title compound as a foam 0.465 g, 93%.

MS (FD ) m/z =430. ¹ H NMR (CDCl₃): δ 7.87 (m, 2H), 7.75 (m, 2H), 5.51(d, 1H), 4.06 (q, 2H), 1.49 (s, 9H), 1.17 (t,3H). ¹³ C NMR (CDCl₃): δ171.95, 167.37, 166.78, 135.69

EXAMPLE 4

1-t-butoxycarbonylmethyl-3β-(2-pyrrolidinecarbonyl)benzoylamino-4.beta.-(2-ethoxycarbonyl)ethan-1-yl-azetidin-2-one

Reaction of pyrrolidine (0.016 mL) with the phthalimide from Example 3(69.3 mg) in tetrahydrofuran (0.20 mL; 25° C., 2 h) provided the titlecompound as a white foam, 79 mg, 98%.

HPLC (Zorbax® C-8,254 nm) 98% integration TLC: Rf, 0.21 (ethylacetate-hexane, 2:1).

EXAMPLE 5

1-t-Butoxycarbonylmethyl-3β-(2-pyrrolidinocarbonyl)benzoylamino-4β-(2-ethoxycarbonyl)ethyleneoxide-1-yl-azetidin-2-one

Reaction of a (200 mg) sample of the material from Example 1 intetrahydrofuran (3.0 mL ) with pyrrolidine (40 μL, 25° C., 3 h) affordedthe 228 mg of the title compound as a foam after evaporation of thesolvent and vacuum drying.

TLC: Rf, 0.67 (ethyl acetate-hexane-methanol, 1:1:1). AnalysisCalculated for C₂₂ H₂₄ N₂ O₈ N₉ : Calc.: C, 60.57; H, 6.45; N, 8.15;Found: C, 60.80; H, 6.44; N, 7.91. MS (FD) m/z=515 (100%). ¹ H NMR(DMSO-d₆): δ 9.33 (d, 1H), 7.40-7.60 (m, 3H), 7.31 (d, 1H), 5.35 (dxd,1H), 4.08 (m, 1H), 4.04 (dxd, 2H), 3.87 (m, 1H), 3.60 (m, 1H), 3.08(dxd, 2H), 1.82 (m, 4H), 1.47 (s, 9H), 0.94 (t, 3H).

EXAMPLE 6

Sodium1-t-butoxycarbonyl-3-(2-pyrrolidinocarbonyl)benzoylamino-4β-(2-carboxylate)ethylene oxide-1-yl-azetidine-2-one

To the compound of Example 5 (46.0 mg) intetrahydrofuran-acetonitrile-dimethyl sulfoxide (1 mL, 7:7:1) was addeda solution of sodium hydroxide (1N, 0.089 mL, 25° C.) in six portionsover 2 h. All of the solvent was removed in a stream of nitrogen and theresidue dried under high vacuum affording the title compound as a foam.Yield:

TLC: Rf, 0.18 (methanol-ethyl acetate-hexane, 2:1:1) HPLC (Zorbax® C-8,254 nm)>95% integration. ¹ H NMR (DMSO-d₆): δ 9.20 (d, 1H), 7.50 (d,1H), 7.52 (m, 1H), 7.43 (m, 1H), 7.24 (d, 1H), 5.38 (dxd, 1H), 4.17,3.79 (dxd, 2H), 3.48 (dxd, 1H), 3.21 (m, 1H), 3.10 (m, 2H), 2.78 (d,1H), 1.80 (4H), 1.44 (S, 9H). IR (KBr): 1771, 1737 cm⁻¹.

EXAMPLE 7

1-Carboxymethyl-3β-phthaloylamino-4β-(2-ethoxycarbonyl)ethan-1-yl-azetidin-2-one

A solution of 10.4 g of the compound from Example 3 was treated with 85mL of trifluoroacetic acid in methylene chloride (140 mL, 0° C.). Allvolatiles were removed at 0° to -15° C., after reaction completion (6 hat 0° C.). Diethylether (50 mL) was added and the mixture filtered toafford the title compound, (8.30 g, 92%).

m.p. 140-144° C. MS (FD), m/z 375 (M⁺ +1 , 100%) Analysis Calculated forC₁₈ H₁₈ N₂ O₇ : Calc.: C, 57.75; H, 4.84; Found: C, 57.61; H, 5.00; C,57.56; H, 4.79. [α]_(D) =+5.44°, +5.87° (C=1, methanol) [α]₃₆₅ =-24.97°,-25.4° (C=1, methanol) HPLC (Zorbax® C-8, 254 nm)>99% ¹³ C NMR (CDCl₃):δ 14.04, 23.61, 30.74, 42.16, 56.99, 58.60, 123.90, 131.60, 134.67,165.27, 167.48, 170.95, 172.37. ¹ H NMR (CDCl₃): δ 2.65 (1H, broad s),7.90 (m, 2H), 7.80 (2H, m), 5.50 (d, 1H), 4.05 (q, 2H), 1.17 (t, 3H).

EXAMPLE 8

1-(Carboxymethyl)pyrrolidinate-3β-(2-pyrrolidinocarbonyl)benzoylamino-4β-(2-ethoxycarbonyl)ethan-1-yl

To a solution of the compound from. Example 7 (8.00 g) intetrahydrofuran (80 mL) was added pyrrolidine (3.3 mL). After completion(25° C., 2.3 h) of the reaction all solvent was removed under vacuum toafford the title compound as a foam (11.03 g); this compound was used inExample 9 without further purification.

HPLC Analysis (Zorbax® C-8, 254 nm) showed 98.8% integration, partialreversion to phthalimide.

EXAMPLE 9

Disodium-1-(carboxylate)methyl-3β-(2-pyrrolidinocarbonyl)benzoylamino-4β-(2-carboxylate)ethan-1-yl-azetidin-2-one

The title compound from Example 8 (1.00 g) was dissolved intetrahydrofuran-water (60 mL, 5:1 v/v) and treated with sodium hydroxide(1.000N, 3.88 mL added in 5 portions over 2.0 h, 25° C.). HPLC (Zorbax®C-8, 254 nm buffer: methanol-water 1.0:1.85 with 0.05M ammonium acetate)analysis indicated 88-90% yield of desired product. All solvent wasremoved in vacuo and the foam was triturated with ether to afford thetitle compound (830 mg, 85% ).

[α]_(D) =+8.36° (C=1, methanol) [α]₃₆₅ =+35.61° (C=1, methanol) HPLC,85% integration. ¹ H NMR (DMSO-d₆): δ 9.23 (1H, NH), 7.2-7.8 (4H,aromatic ), 5.20 (1H ). MS (FAB) m/z=462.

EXAMPLE 10

1-carboxymethyl-3β-(2-pyrrolidinocarbonyl)benzoyl-amino-4β- (2-carboxy)ethan-1-yl-azetidin-2-one

A 9.74 g sample of the compound of Example 8 was dissolved intetrahydrofuran-water (510 mL, 7.5:1. v/v, 25° C.) and sodium hydroxide(18.9 mL of 1N) was added (3 min) followed by an equal second portion(over 2 h). During the course of this addition (1 h) acetonitrile (100mL) was added. When the reaction was complete, solid carbon dioxide wasadded followed by hydrochloric acid (37.7 mL of 1N, pH=4.0). The aqueousphase was saturated with sodium chloride and was extracted with ethylacetate-methylene chloride (1:1, v/v, 7×200 mL) after which the driedorganic layer (sodium sulfate and 4Å molecular sieves) was evaporated(6.5 g, hygroscopic white foam). Before use this material was trituratedwith ether and vacuum dried).

HPLC (Zorbax®RX, 254 nm) 72% integration.

EXAMPLE 11

Diphenyl 1-(carboxylate)methyl-3β-(2-pyrrolidinocarbonyl)benzoylamino-4β-(2-carboxylate)ethan-1-yl-azetidin-2-one

Treatment of the diacid (2.41 g) from Example 10 with a mixture ofphenol (2.1 equiv), 4-dimethylaminopyridine (0.2 equiv.) withdicyclohexylcarbodimide (2.50 g) in methylene chloride-dimethylformamide(20 mL, 1:1 v/v) provided 3.29 g of impure diphenyl ester. Preparativeliquid chromatography employing step elution with ethyl acetate/hexaneafforded the title compound.

TLC: Rf, 0.55 (ethyl acetate-hexane, 1:1). ¹³ C NMR (CDCl₃): δ carbonylsat 171.36, 169.7, 168.0, 166.6, 166.5. Aromatic carbons at 150.6, 150.1,136.6, 131.6, 131.4, 129.6, 129.5, 129.4, 129.3, 126.5, 126.31, 125.9,121.6, 121.3. IR (CHCl₃): 3400 (weak), 1760, 1664, 1218 cm⁻¹. ¹ H NMR(CDCl₃): δ 8.05 (d, 1H), 7.91 (d, 1H), 7.00 to 7.60 (m, 13H), 5.53 (dxd,1H, cis), 4.55 (d, 1H), 4.23 (m, 2H), 4.12 (d, 1H), 3.6-3.8 (m, 2H),3.12 to 3.27 (m, 2H), 2.58 to 2.75 (m, 2H), 2.09 to 2.3 (m, 1H), 1.80 to2.11 (m, 5H). MS(FD) m/z =569 (M⁺ 100%).

EXAMPLE 12

1-(p-Nitrobenzylcarboxylate)methyl-3β-(2-pyrrolidinocarbonyl)benzoylamino-4β-(2-phenylcarboxylate)-ethan-1-yl-azetidin-2-one

To solution of the diester (169 mg) from Example 11 in p-nitrobenzylalcohol in tetrahydrofuran (20 mL) was added sodium tert-butoxide(0.645M in tetrahydrofuran, 0.020 mL added in 6 portions at -10° to -20°C. over 18 h). Acetic acid (2 μL) was added and all solvent removed invacuo. Chromatography over silica gel (20 g, gradient elution with ethylacetate-hexane-methanol) afforded 161 mg (80%) of the title compound asa solid foam.

MS (FD) m/z =628 (M⁺). TLC: Rf, 0.28 (ethyl acetate-hexane, 1:1). ¹ HNMR (CDCl₃): δ 8.33 (d, 2H), 8.17 (d, 1H), 7.83 (d, 1H), 7.13 to 7.55(m, 8H), 6.98 (d,2H), 5.43 (dxd, 1H), 5.21 (2H, s), 4.30 (d, 1H), 4.11(m, 1H), 3.86 (d, 1H), 3.50 to 3.78 (m, 2H), 3.17 (m, 2H), 2.40 to 2.70(m, 2H), 2.01 to 2.17 (m, 1H), 1.86 to 1.99 (m, 5H).

EXAMPLE 13

p-Nitrobenzyl-7β-(2-pyrrolidinocarbonyl)benzoylamino-1-carba(dethia)-3-hydroxy-3-cephem-4-carboxylate

To a solution of sodium tert-butoxide in tetrahydrofuran (0.59 mL, 0.68M, ≦-70° C.) was added the diester (50 mg) prepared in Example 12 whichwas dissolved in 1.0 mL of tetrahydrofuran which had been precooled to≦-70° C. After which (total of 3 min at -78° C.) the solution was pouredonto ice (25 g) and washed with hydrochloric acid (2N, 25 mL). Theaqueous phase was back extracted (methylene chloride, 50 mL) after whichthe combined organic extracts were dried over sodium sulfate andevaporated. The product (white foam) was triturated with t-butyl methylether (about 0.1 mL) and purified by silica gel chromatography (ethylacetate, toluene, acetic acid, 4:7:1).

STLC: Rf 0.36; integration >95% (260 nm) [α]₃₆₅ =+246° (C=0.05,methanol) MS (FD ), m/z =534 (100%). ¹ H NMR (CDCl₃, overlays with aboveexample):

CD (EtOH), [θ]₂₈₀ =+6500, [θ]₂₃₂ =0; [θ]₂₁₇ =-13,750

Preparation 2

p-Nitrobenzyl 7β[phthalisoimido]-1-carba(dethia)3 -chloro-3-cephem-4-carboxylate

To a stirred mixture of p-nitrobenzyl7β-amino-1-carba(1-dethia)-3-chloro-3-cephem-4-carboxylate (10 g),methylene chloride (1 L), water (50 mL), and sodium bicarbonate (5.98 g)was added phthaloyl dichloride (5.00 mL) at 5-7° C. over 20 min. Afterstirring 45 min, methanol was added (15 min, 5-7° C.) followed by aceticacid (pH 7, 1.62 g). At 5° C. the organic layer was washed (50 mL 50%brine, 50 mL of saturated brine), dried (10 g, 4Å molecular sieves, 20min), and evaporated to an oil (16 g). Addition of 100 mL of etherprompted crystallization of the title compound (10.15 g, 80%). A secondcrop was collected from 50 mL ether (2.639 g, total yield >90%)

TLC: Rf, streak to 0.4 (ethyl acetate-hexane, 1:1) m.p. 140-145° C.(decomposes). IR (CHCl₃) 1777, 1735, 1705 cm⁻¹ (No-OH or --NH). [α]_(D)²⁵ =-156 6° (C=1, CHCl₃) UV (EtOH), λX(E): 266 (21400), 215(27600). ¹³ CNMR (CDCl₃): δ 22.72, 31.97, 52.49, 66.21, 66.38, 123.37, 123.63,123.77,125.57, 128.23, 128.84, 130.65, 130.70, 133.58, 135.61, 142.39, 147.84,152.08, 160.18, 163.72, 164.08. MS (FD) m/z=481.5 (M⁺), 483.5 (M⁺ +2) ¹H NMR (Acetone-d₆): δ 5.67 (d, H), 5.48 (dxd, 2 H) 4.18 (dxd), 2.23 (m,2H).

Preparation 3

p-Nitrobenzyl-7β-phthaloylamino-1-carba(dethia)-3-chloro-3-cephem-4-carboxylate

A mixture of p-nitrobenzyl7β-[2-[(1-pyrrolidino)-carbonyl]phenyl]carbonylamino-1-carba(1-dethia)-3-chloro-3-cephem-4-carboxylate(2.00 g) dissolved in tetrahydrofuran-water (10:1 v/v, 22 mL) containingboric acid (2.0 g) and hydrofluoric acid (48%, 1 mL) was allowed toreact (25° C., 96 h) after which additional hydrofluoric acid (1 mL) andboric acid (2 g) were added. After stirring (25° C., 5 min.) the firstcrop of product was collected and in a like manner a second crop wascollected (after 24 h, 25° C.). The filtrate was evaporated in vacuo andstarting material recovered (1.1 g, 55%) after trituration with water(30 mL), filtration, and drying. The combined first and second crops ofproduct were purified by chromatography (40 g silica, elution with 40%ethyl acetate in methylene chloride) affording the title compound (700mg, >90% based on recovered starting material).

HPLC: (Zorbax® C-8, 254 nm) 96.9% integration corrected for solventabsorbance. IR(CHCl₃) 1726, 1387 cm⁻¹. m.p. 186-191° C. MS (FD), m/z481. ¹³ C NMR(CDCl₃): δ 21.76, 31.90, 53.14, 56.91, 66.33, 123.50,123.76, 123.97, 128.95, 130.25, 131.47, 134.82, 142.32, 147.87, 160.02,161.02, 167.35. ¹ H NMR(CDCl₃, partial): δ 5.53 (1H, d) 5.43 (dxd, 2H),4.03 (1H, m), 2.69 (m, 2H) UV (ethanol)λ(E) 272 (19300), 243 (15100),220 (45600). [α]_(D) ²⁵ =-37.5° (C=1, CHCl₃)

Preparation 4

p-nitrobenzyl-7β-phthaloylamino-1-carba(dethia)-3-chloro-3-cephem-4-carboxylate

To a solution of triphenylphosphite (0.1 mL) in methylene chloride (1.0mL, -30° C.) was added a slight excess of chlorine (<5 min). Excesschlorine was discharged with amylenes and this solution was added top-nitrobenzyl-7β-(2-pyrrolidinocarbonyl)benzoylamino-1-carba(dethia)-3-hydroxy-3-cephem-4-carboxylatein ethyl acetate (1.0 mL) and pyrimidine (0.025 mL, -40° C.). Additionalsolvent (2 mL, methylene chloride) was added and the mixture was warmed(-20° C., 0.5 h; 0° C., 1 h; 25° C., 2 h). After which, the mixture wasquenched with water (1 mL, 25° C. , 1 h). Analysis by HPLC indicatedabout 68% of 3-chloro-phthalimide admixed with about 32% of3-chloro-orthopyrrolidinocarbonylbenzamide (acyl-protected-3-chloro)(total yield estimated from HPLC=60%). The above extracts were washedwith hydrochloric acid (0.1N, 2 ×1 mL), water (2 ×1 ml) and dried withsodium sulfate. Evaporation of solvents and purification (preparativethin layer chromatography, ethyl acetate-toluene-acetic acid, 4:7:1)afforded the title compound.

MS (FD), m/z=480.7 (M+), 482.7 (M⁺ +2, 35%). ¹ H NMR, TLC; and HPLC wereidentical to the example above (derived in turn from material preparedaccording to the reference of Bodurow, et al., Tetrahedron Lett. 1989,30, 2321).

Preparation 5

7β-Phthaloylamino -1-carba(dethia)-3 -chloro-3-cephem-4-carboxylic acid

A solution of the p-nitrobenzyl ester (155 mg) from Preparation 4 washydrogenated (1 atm, 25° C. 2.5 h) in tetrahydrofuran-acetic acid-water(5:1:0.075, 6 mL) with palladium on carbon (5% w/w, 8.2 mg). Afterfiltration, the solvent was removed in a nitrogen stream and the residuedissolved in ethyl acetate (75 mL). Normal extractive work-up involvingwashing (3×25 mL of 0.1 N HCl), back-extraction (25 ml ethyl acetate),drying (4A molecular sieves), and solvent evaporation afforded the acid(120 mg, 100%).

[α]_(D) ²⁵° =-33.5° (C=1, methanol) UV (EtOH): λ(E), 221, (40800), 263(10900) MS (FD) m/z=346 m.p. 230°-234° C. (decomposition) HPLC(Zorbax®RX, 254 nm) 99.6% integration IR (KBr) 3183, 1768, 1729 cm⁻¹TLC: Rf, 0.27 (Toluene-ethyl acetate-acetic acid, 5:5:1) AnalysisCalculated for C₁₆ H₁₁ ClN₂ O₅ : Calc.: C, 55.43; H, 3.20; N, 8.08; O,23.07; Cl, 10.23. Found: C, 55.67; H, 3.36; N, 7.89; O, 23.19; Cl,10.07.

EXAMPLE 14

p-Nitrobenzyl7β-(2-pyrrolidinocarbonyl)benzoylamino-1-carba(dethia)-3-chloro-3-cephem-4-carboxylate

The isoimide (7.50 g) from Preparation 2 was dissolved intetrahydrofuran (-12° C.) and treated with pyrrolidine (1.30 mL, -10° C.to -14° C., 45 min). All volatiles were removed in vacuo, dry ether (125mL) was added, and the title compound collected by filtration (8.03 g,93% after drying).

[α]₅₈₉ =-8.67° (C =1, CHCl₃). IR (CHCl₃) 3400 (weak, NH), 1778, 1735cm⁻¹. MS, 553.5 (M⁺ +1, 100%), 48.4 (M⁺ -pyrrolidine) HPLC: (Zorbax®RX,254 nm) 96.9% integration ¹ H NMR (CDCl₃): δ 8.23 (d, 2H), 8.21 (d, 1H),5.61 (dxd, 1H) 5.38 (dxd, 2H), 3.86 (m, 1H), 2.63 (m, 2H) ¹³ C NMR(CDCl₃): δ carbonyls at 160.13, 165.18, 167.62, 169.8 m.p. 120-125° C.TLC: Rf, 0.42 (ethyl acetate-toluene-acetic acid, 4:7:1).

EXAMPLE 15

1-t-Butoxycarbonyl-3β-(2-(R)-1-p-nitrophenylethylaminocarbonyl)benzoylamino-4β- (1,1-dimethoxy)prop-2-ene-3-ylazetidin-2-one

A 110 mg sample of1-t-butoxycarbonylmethyl-3β-phthaloyl-4β-(1,1-dimethoxy)prop-2-ene-3-yl-azetidin-2-one(and 3,4,α,α isomer mixture) and (R)-1-para-nitrophenylethylamine (50mg) were allowed to react in tetrahydrofuran (1.00 mL, 25° C., 8d) afterwhich the soluent was removed in vacuo and the acetal isolated byextractive work-up with ethyl acetate, hydrochloric acid (0.1N), andsodium bicarbonate. Solvent evaporation provided 154 mg (100%) of thetitle compound.

TLC: Rf, 0.68 (10:10:1 ethyl acetate, hexane, methanol ) UV (EtOH) λ (ε)271 (11000). MS (FD) m/z =596. Analysis Calculated for C₃₀ H₃₆ N₄ O₉ :Calc.: C, 60.39; H, 6.08; N, 9.39; Found: C, 60.17; H, 6.08; N, 9.13. ¹H NMR (CDCl₃, partial): δ 8.18 (d, 2H), 7.87 (d, 0.5H), 7.83 (d, 0.5H),3.28, 3.26, 3.24, 3.23 (four s, 1.5 H each ), 1.49, 1.46 (2 s, 4.5 Heach ). ¹³ C NMR (CDCl₃): δ carbonyls 169.8, 169.4, 168.0 167.7, 166.6.

EXAMPLE 16

1-(2,4-dimethoxybenzyl)-3β-2-(S-(+)-2-methoxymethylpyrrolidinocarbonyl)benzoylamino-4β-(2-phenyl)-ethene-1-yl-azetidin-2-one

A solution of1-(2,4-dimethoxypheny1)-3β-phthaloyl4β-(2-phenyl)ethene-1-yl-azetidin-2-one(and3,4,α,α isomer mixture) (2.34 g), S-(+)-2-methoxymethyl pyrrolidine(0.69 g), dimethylformamide/tetrahydrofuran (1:1, 10 mL) was allowed toreact (25° C., 7 d) after which all solvent was removed in a stream ofnitrogen (25° C., 1d). Vacuum drying produced a foam (2.9 g, 100%), 98%pure by HPLC.

UV (EtOH) λ 251 (ε=20,000) [α]_(D) ²⁵° =36.39°, [α]₃₆₅ =-152.35° (C-1,methanol) MS (FD) m/z =583 (M+), 469,354. ¹³ C NMR (DMSO-d₆): δ 55.12,55.4 (diasteromeric methyls of methoxy methylpyrrolidineamide, 1:1) TLC:Rf, 0.23 (ethyl acetate-toluene-acetic acid, 7:4:1) IR (CHCl₃): 1753,1720 absent (present in phthalimido starting material), 1665 (amide),3438 (weak NH). ¹ H NMR (DMSO-d₆): δ 9.15 (two d, 0.5 ea), 5.37 (twodxd, 0.5H ea) 3.28 (S, 1.5H), 3.32 (1.5H).

EXAMPLE 17

1-(2,4-dimethoxybenzyl)-3-phthaloylamino-4-(2-phenyl)-ethene-1-yl-azetidin-2-one

A solution of (mixture of 1:1 cis-β-lactam diastereomers, 500 mg fromexample 16), boric acid (195 mg), hydrofluoric acid (187 mg),tetrahydrofuran-water (9:1, 13 mL) were allowed to react at 25° C.Progress of the reaction was followed by HPLC on a Zorbax®RX column withmethanol-water-triethylamine-ammonium acetate (2400 mL:1200 mL: 40 mL:30g, then pH to 6 with acetic acid) at 0.5 mL/min at 254 nm (slow reactingisomer=35 min, fast reacting isomer=43 min, phthalimide product=49 min).After 120 h, HPLC analysis suggested about a 10:1 ratio of slow/fastreacting isomers and about 65% conversion into the correspondingphthalimide product. All solvent was removed in vacuo and methylenechloride was added. Extractive work-up involving water, aqueous sodiumbicarbonate and drying (sodium sulfate) afforded a white foam. A portion(400 mg) of this material was purified by chromatography on silica(toluene-ethyl acetate-acetic acid 10:4:1) affording the slow reactingisomer. (This intermediate contained about 9% of the fast reactingisomer (average as calculated from ¹ H NMR and HPLC assay data).

¹ H NMR (CDCl₃): δ 5.63 (d, 1H), 5.38 (dxd) 7.6 to 8.3 (mx, 8H), 4.03(1H, m), 2.71 (m, 2H), 2.20 (mx, 2H).

I claim:
 1. A compound of the formula ##STR22## wherein R* is a group ofthe formula ##STR23## wherein R and R⁰ are individually C₁ -C₆ alkylgroups or together form a ring consisting of the nitrogen atom to whichthey are attached and two to seven carbon atoms, said ring optionallysubstituted by one or more C₁ -C₆ alkyl and/or C₁ -C₇ substituted alkylgroups;Q and Q' are individually hydrogen, C₁ -C₆ alkyl, or when takentogether form a divalent radical of the formula --CH═CH--CH═CH--; A andA' together form a group of the formula ##STR24## wherein R² is hydrogenor a carboxy-protecting group; x is sulfur; R¹ is hydrogen, hydroxy,halo, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, C₁ -C₆ substituted alkyl, C₁ -C₆alkylthio, C₁ -C₆ substituted alkylthio, C₇ -C₁₂ phenylalkyl, C₇ -C₁₂substituted phenylalkyl, phenyl or substituted phenyl; a group of theformula

    --COR.sup.3

wherein R³ is hydrogen, C₁ -C₆ alkyl, C₁ -C₆ substituted alkyl, C₇ -C₁₂phenylalkyl, C₇ -C₁₂ substituted phenylalkul, phenyl, substitutedphenyl, amino, (monosubstituted)-amino, or (disubstituted)-amino; agroup of the formula

    --COOR.sup.4

wherein R⁴ is hydrogen, C₁ -C₆ alkyl, C₁ -C₆ substituted alkyl, C₇ -C₁₂phenylalkyl, C₇ -C₁₂ substituted phenylalkyl, phenyl, substitutedphenyl, or a carboxy-protecting group.
 2. A compound of claim 1, whereinthe --NRR⁰ group is pyrrolidino.